Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response.

Neoadjuvant immune-checkpoint blockade therapy only benefits a limited fraction of patients with glioblastoma multiforme (GBM). Thus, targeting other immunomodulators on myeloid cells is an attractive therapeutic option. Here, we performed single-cell RNA sequencing and spatial transcriptomics of patients with GBM treated with neoadjuvant anti-PD-1 therapy. We identified unique monocyte-derived tumor-associated macrophage subpopulations with functional plasticity that highly expressed the immunosuppressive SIGLEC9 gene and preferentially accumulated in the nonresponders to anti-PD-1 treatment. Deletion of Siglece (murine homolog) resulted in dramatically restrained tumor development and prolonged survival in mouse models. Mechanistically, targeting Siglece directly activated both CD4+ T cells and CD8+ T cells through antigen presentation, secreted chemokines and co-stimulatory factor interactions. Furthermore, Siglece deletion synergized with anti-PD-1/PD-L1 treatment to improve antitumor efficacy. Our data demonstrated that Siglec-9 is an immune-checkpoint molecule on macrophages that can be targeted to enhance anti-PD-1/PD-L1 therapeutic efficacy for GBM treatment.

Knockdown of HDAC1 expression suppresses invasion and induces apoptosis in glioma cells.

Glioma is the most common malignant tumor of the central nervous system, with a low survival rate of five years worldwide. Although high expression and prognostic value of histone deacetylase 1 (HDAC1) have been recently reported in various types of human tumors, the molecular mechanism underlying the biological function of HDAC1 in glioma is still unclear. We found that HDAC1 was elevated in glioma tissues and cell lines. HDAC1 expression was closely related with pathological grade and overall survival of patients with gliomas. Downregulation of HDAC1 inhibited cell proliferation, prevented invasion of glioma cell lines, and induced cell apoptosis. The expression of apoptosis and metastasis related molecules were detected by RT-PCR and Western blot, respectively, in U251 and T98G cells with HDAC1 knockdown. We found that HDAC1 knockdown upregulated expression of BIM, BAX, cleaved CASPASE3 and E-CADHERIN, and decreased expression of TWIST1, SNAIL and MMP9 in U251 and T98G cells with HDAC1 knockdown. In vivo data showed that knockdown of HDAC1 inhibited tumor growth in nude mice. In summary, HDAC1 may therefore be considered an unfavorable progression indicator for glioma patients, and may also serve as a potential therapeutic target.

New Insights in Minimally Invasive Surgery for Intracerebral Hemorrhage.

The poor clinical outcome of acute intracerebral hemorrhage (ICH) relates closely to the bleeding amount per unit of time and the hematoma position in the brain. Removal of an intracerebral hematoma in time can effectively improve clinical prognosis. Minimally invasive surgery (MIS) for the treatment of ICH is the main clinical method that is currently used, despite the lack of large-scale, clinical, multi-center, randomized controlled trials. This article comprehensively reviews the history and development of MIS for ICH and analyzes various roles of MIS in ICH treatment. General CT image-guided surgery with the local use of thrombolysis techniques is a major MIS method used in current ICH treatment.

Brain cancer surgery in the language areas of Mandarin-Cantonese bilinguals.

OBJECTIVE: This study aimed to study methods for protecting the language areas during tumor surgery in Mandarin-Cantonese bilinguals (MCBs). MATERIALS AND METHODS: Eleven MCB patients were positioned for awake surgery with the purpose of preserving both of their language proficiencies. All the exposed cortices were electrically stimulated 1 cm x 1 cm with anelectrode, and all the positive sites of stimulation were recorded for analyses, the tumor resection point was limited by 1cm distant from the language areas identified by electrical stimulation. RESULTS: All patients had at least one language area identified; a total of 154 points were stimulated, with 22 positive points (14.3%), including five specific language areas, which all resulted in simple anomiain either language when stimulated. Among these, three were specific to Mandarin (1.9%), whereas two were specific to Cantonese (1.3%). CONCLUSIONS: In proficient MBCs, areas specific to each language exist. Thus, performing intraoperative bilingual tasks to locate these language areas is necessary in order to preserve language function.

Malignant transformation of craniopharyngioma with detailed follow-up.

A 29-year-old male patient was admitted into hospital with the main complaint of progressive visual disturbance. Both CT SCAN and MRI demonstrated a cystic-solid contrast-enhancing sellar-suprasellar mass with obvious calcification. Histopathological examination of the first resected specimen showed a typical appearance of adamantinomatous craniopharyngioma. The patient received gamma knife therapy after his first operation because of partial tumor removal. He experienced two relapses in the subsequent 2 years, for which only surgical resection was performed. The later histopathology presented malignant appearance with tumor cells moderate to severe pleomorphism, hyperchromasia, increased nuclear cytoplastic ratio, high mitotic activity (30/10 high power fields) and focal coagulative necrosis. The patient died 9 months after identification of histologic malignancy. Clinical and histopathological features, biological behavior of one case of malignant craniopharyngioma were discussed, with a brief review of the relevant literature.

[Brain mappings in non-fluent late Chinese-English bilinguals].

OBJECTIVE: To discuss the distribution characteristics of language areas in Chinese-English non-fluent late bilinguals. METHODS: Six Chinese-English bilinguals with eloquent tumors underwent awake-surgeries. The activated areas of BOLD-fMRI were obtained as the patients performed pure naming, verb generation, and abstract/concrete judgment tasks. Direct cortical stimulation(DCS) as the golden standard of language mapping were performed during awake-surgeries on the exposed cortical areas. BOLD-fMRI results of 3 language tasks were compared with DCS results. The statistical method was McNemer. RESULTS: Sixteen positive sites(22.5%) were comfirmed out of 71 stimulations. There were 3 specific language sites, in which 2 sites were specific English sites and 1 site was specific Chinese site. When activated areas of BOLD-fMRI were compared with the DCS results, verb generation task had the highest concordance rate 40.9% (95%CI:30.2%-52.5%) . There were significant differences between the results of BOLD-fMRI and DCS of all 3 bilingual tasks(P < 0.017). CONCLUSIONS: There are specific language areas in Chinese-English non-fluent late bilinguals. The BOLD-fMRI language mapping could not substitute DCS in the context of mapping language areas in bilinguals.

The modulation of venlafaxine on cortical activation of language area in healthy subjects with fMRI study.

RATIONALE: Previous studies have shown that selective serotonin reuptake inhibitors, activators of the cortex, apparently improved language functional recovery after brain damage rather than simply affective disorders. OBJECTIVE: Our aim was to determine whether venlafaxine (an agonist of both norepinephrine and 5-hydroxytryptamine) could modulate language cortex function. METHODS: A double-blind, crossover, randomized design was used to compare two 7-day treatment sessions with either venlafaxine (75 mg per day) or placebo. A functional magnetic resonance imaging experiment and two language function tests were performed on eight healthy males (mean age, 28.25 ± 3.15 years) at the end of each session, i.e., study entry, after venlafaxine, and after placebo (days 0, 7, and 18). Hyperactivation (venlafaxine minus placebo >0) or hypoactivation (placebo minus venlafaxine >0) by venlaxafine was assessed on the basis of the activation-baseline contrast. RESULTS: The naming score (P < .001) and spontaneous language fluency (P < .001) were significantly higher after venlafaxine than after placebo. Functional magnetic resonance imaging (fMRI) showed that (1) picture naming activated the left posterior gyrus frontalis medius and the bilateral fusiform gyrus and the bilateral outer occipital lobes, (2) hyperactivation was observed in the adjoining area of posterior upper Broca area and premotor area in the dominant hemisphere in venlafaxine session (after venlafaxine), (3) the hyperactivation of the left gyrus frontalis medius on fMRI and the increase in naming test score were positively correlated, and (4) by contrast, we observed hypoactivation in the temporo-parieto-occipital region in venlafaxine session (after venlafaxine). This improvement may be related to increased phonics-related output in the frontal language cortex of the dominant hemisphere.

Three core techniques in surgery of neuroepithelial tumors in eloquent areas: awake anaesthesia, intraoperative direct electrical stimulation and ultrasonography.

BACKGROUND: The goal of surgery in the treatment of intrinsic cerebral tumors is to resect the maximum tumor volume, and to spare the eloquent areas. However, it is difficult to discover the eloquent areas intraoperatively due to individual anatomo-functional variability both for sensori-motor and language functions. Consequently, the surgery of intrinsic cerebral tumors frequently results in poor extent of resection or permanent postoperative deficits, or both, and remains a difficult problem for neurosurgeons. METHODS: From January 2003 to January 2010, 112 patients with neuroepithelial tumors in/close to the eloquent areas were operated on under awake anesthesia with the intraoperative direct electrical stimulation for functional mapping of the eloquent areas. The extent of the tumors was verified by intraoperative ultrasonography. The maximal resection of the tumors and minimal damage of the eloquent areas were the surgical goal of all patients. RESULTS: Totally 356 cortical sites in 99 patients were detected for motor response by intraoperative direct electrical stimulation, 50 sites in 16 patients for sensory, 72 sites in 48 patients for language. Sixty-six patients (58.9%) achieved total resection, 34 (30.4%) subtotal and 12 (10.7%) partial. Fifty-eight patients (51.8%) had no postoperative deficit, while 37 patients (33.0%) had transitory postoperative paralysis, 26 patients (23.2%) with transitory postoperative language disturbance and 3 patients (2.7%) with permanent neurological deficits. No patient complained of pain recollection following operation. CONCLUSIONS: Awake anesthesia, intraoperative direct electrical stimulation and ultrasonography are three core techniques for the resection of intrinsic cerebral tumors near the eloquent areas. This new concept allows an improvement in the quality of surgery for neuroepithelial tumors in/adjacent to eloquent areas.

Functional MRI mapping of category-specific sites associated with naming of famous faces, animals and man-made objects.

OBJECTIVE: Category-specific recognition and naming deficits have been observed in a variety of patient populations. However, the category-specific cortices for naming famous faces, animals and man-made objects remain controversial. The present study aimed to study the specific areas involved in naming pictures of these 3 categories using functional magnetic resonance imaging. METHODS: Functional images were analyzed using statistical parametric mapping and the 3 different contrasts were evaluated using t statistics by comparing the naming tasks to their baselines. The contrast images were entered into a random-effects group level analysis. The results were reported in Montreal Neurological Institute coordinates, and anatomical regions were identified using an automated anatomical labeling method with XJview 8. RESULTS: Naming famous faces caused more activation in the bilateral head of the hippocampus and amygdala with significant left dominance. Bilateral activation of pars triangularis and pars opercularis in the naming of famous faces was also revealed. Naming animals evoked greater responses in the left supplementary motor area, while naming man-made objects evoked more in the left premotor area, left pars orbitalis and right supplementary motor area. The extent of bilateral fusiform gyri activation by naming man-made objects was much larger than that by naming of famous faces or animals. Even in the overlapping sites of activation, some differences among the categories were found for activation in the fusiform gyri. CONCLUSION: The cortices involved in the naming process vary with the naming of famous faces, animals and man-made objects. This finding suggests that different categories of pictures should be used during intra-operative language mapping to generate a broader map of language function, in order to minimize the incidence of false-negative stimulation and permanent post-operative deficits.

Reduced expression of LC3B-II and Beclin 1 in glioblastoma multiforme indicates a down-regulated autophagic capacity that relates to the progression of astrocytic tumors.

The aim of this study was to investigate the expression of microtubule-associated protein 1 light chain 3B (LC3B) and the autophagy-related gene Beclin 1 in astrocytic tumors and to analyze their expression profiles with respect to the development of astrocytic tumors. The expression patterns of LC3B and Beclin 1 were analyzed by immunohistochemistry and/or western blotting in tumor samples from 62 patients with different grades of astrocytic tumor. The expression patterns of LC3B and Beclin 1 were correlated with the pathological and clinical characteristics of the patients. Western blot analysis indicated that the average optical densitometry (OD) ratio of Beclin 1 in high-grade astrocytic tumors (World Health Organization [WHO] grade III/IV) was lower than in low-grade astrocytic tumors (WHO grade I/II, p = 0.036). The expression of LC3B-I exhibited no significant difference among the various grades of astrocytic tumor. However, the average OD ratio of LC3B-II was lower in glioblastoma multiforme (GBM) than in other grades of astrocytic tumor (p = 0.030). The expression levels of Beclin 1 and LC3B-II were related to survival time and they were also correlated with each other (p = 0.035). In addition, down-regulation of LC3B-II and Beclin 1 expression was associated with GBM. The progression of astrocytic tumors was related to a decrease in autophagic capacity represented by the loss of LC3B-II and Beclin 1 expression.

Posttraumatic secondary brain insults exacerbates neuronal injury by altering metabotropic glutamate receptors.

BACKGROUND: Our previous studies indicated that metabotropic glutamate receptors (mGluRs) are deeply involved in the secondary processes after diffuse brain injury (DBI). In the present study, we used a rodent DBI model to determine whether hypotension exacerbates neuronal injury as a secondary brain insult (SBI) after traumatic brain injury (TBI) by changing the expression of metabotropic glutamate receptors (mGluRs) in the cerebral cortex. RESULTS: Three hundred and eleven male Sprague-Dawley rats were randomly assigned into five groups: normal control, sham-operated control, SBI alone, DBI alone, or DBI with SBI. DBI was produced in rats by Marmarou's methods and the SBI model was produced by hypotension. The alteration of neuronal expression of mGluRs after DBI and DBI coupled with SBI was observed by hybridization in situ at different time points in the experiment. We found a higher mortality and neurological severity score (NSS) for rats in the DBI with SBI group compared with those in the DBI alone group. Although there was a significant rise in the expression of group I and group III mGluRs (except mGluR6) and a decrease in the expression of group II mGluRs after DBI (P < 0.05), the changes were more severe when DBI was coupled with SBI (P < 0.05). The expression of group I mGluRs peaked at 24 hours, while the expression of the group III mGluRs peaked at 6 hours after injuries, which may reflect a self-protection first mechanism of the damaged neurons. Moreover, the overall neuro-harmful effects of mGluRs on neurons were seemly associated with higher mortality and NSS in the DBI with SBI group. CONCLUSION: The results suggest posttraumatic SBI may exacerbate neuronal injury or brain injury by altering expression of mGluRs, and more emphasis should therefore be put on the prevention and treatment of SBI.

Metabotropic glutamate receptor antagonists and agonists: potential neuroprotectors in diffuse brain injury.

Our previous study has suggested that metabotropic glutamate receptors (mGluRs) were significantly involved in the secondary processes after diffuse brain injury (DBI) and that mGluRs antagonists or agonists may be used for the treatment of DBI. In the present study, the neuroprotective effects of antagonists or agonists of mGluRs on DBI were further investigated. Sprague-Dawly rats were randomized into the following six groups: (i) normal control; (ii) sham-operated control; (iii) DBI; (iv) DBI treated with normal saline (NS); (v) DBI treated with alpha-methyl-4-carboxy-phenylglycine (MCPG); and (vi) DBI treated with (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV). Animals were injected intracerebroventricularly (icv) with 10 microL MCPG (100mmol/L), DCG-IV (10nmol/L) or the equivalent volume of normal saline 1 h after injury. The neurological severity score (NSS), brain water content and the number of damaged neurons were determined 6, 12, 24, 72 and 168 h after injury. In rats with DBI, it was found that the NSS was improved and the water content in the frontal cortex and the number of damaged neurons in the parietal cortex were significantly reduced following icv injection of either MCPG or DCG-IV. This suggests that icv injection of the mGluR group I antagonist MCPG or the mGluR group II agonist DCG-IV may exert neuroprotective effects in the early stage after DBI.

Altered expression patterns of metabotropic glutamate receptors in diffuse brain injury.

The metabotropic glutamate receptors (mGluRs), as one of the newly found glutamate receptors, play an important role in the physiological processes of the central nervous system. The authors examined the changes of expression patterns of mGluRs after diffuse brain injuries (DBI) in rats. DBI was produced by Marmarou's methods. The mRNA expression of mGluRs was detected by hybridization in situ at different time points after brain injuries. Compared with normal control and sham-operated control, the animals with DBI showed a significantly increased expression of group I and group III mGluRs (except mGluR6, P<0.05). The increased peak of group I appeared at 24 h after injuries and group III at 6 h after injuries. While, group II mGluRs decreased after DBI (P<0.05) and the lowest point occurred at 48 h after DBI. The difference of time sequence of the expression alterations between group I and group III mGluRs may reflect a self-protection first mechanism of the damaged neurons. It may provide new insight for the development of new pharmaceuticals in the treatment of DBI.

Changes in metabotropic glutamate receptor 4 expression and the effects of L-2-amino-4-phosphonobutyrate in a rodent model of diffuse brain injury.

OBJECTIVE: To examine the changes in the expression of mGluR4 after diffuse brain injury (DBI) and to determine the role of its specific agonist L-2-amino-4-phosphonobutyrate (L-AP4) in vivo. METHODS: A total of 161 male SD rats were randomized into the following groups. Group A included normal control, sham-operated control and DBI group. DBI was produced according to Marmarou's diffuse head injury model. mRNA expression of mGluR4 was detected by hybridization in situ. Group B included DBI alone, DBI treated with normal saline and DBI treated with L-AP4. All DBI rats were trained in a series of performance tests, following which they were subjected to DBI. At 1 and 12 hours, animals were injected intraventricularly with L-AP4 (100 mmol/L, 10 microl) or normal saline. Motor and cognitive performances were tested at 1, 3, 7, 14 days after injury and the damaged neurons were also detected. RESULTS: There was no significant difference between normal control group and sham-operated group in the expression of mGluR4 (P>0.05). The animals exposed to DBI showed significantly increased expression of mRNA of mGluR4 compared with the sham-operated animals 1 h after injury (P<0.05). At 6 hours, the evolution of neuronal expression of mGluR4 in the trauma alone group was relatively static. Compared with saline-treated control animals, rats treated with L-AP4 showed an effective result of decreased number of damaged neurons and better motor and cognitive performances. CONCLUSIONS: Increased expression of mGluR4 is important in the pathophysiological process of DBI and its specific agonist L-AP4 can provide remarkable neuroprotection against DBI not only at the histopathological level but also in the motor and cognitive performance.

[Changes and effects of group II metabotropic glutamate receptors in the cerebral cortex of rats after diffuse brain injuries coupled with hypopiesia secondary brain insults].

OBJECTIVE: To study the changes and effects of group II metabotropic glutamate receptors (mGluR) after diffuse brain injuries (DBI) coupled with hypopiesia secondary brain insults (SBI). METHODS: Male SD rats were randomized into four groups: normal control, sham-operated, DBI alone and DBI coupled with SBI group. The SBI model was made on the basis of Marmarou's model. The mRNAs of the mGluRs were detected at 1, 3, 6, 12, 24, 48 and 72 hours after injuries by in-situ hybridization, and the positive neurons were counted. RESULTS: Statistical analysis showed no significance between normal control group and sham-operated group, DBI group in mGluR 2, 3 mRNA (all P>0.05). The number of mGluR 2, 3 positive neurons decreased at 12 hours after injury and the peak occurred at 48 hours after injury in the injured cerebral cortex in DBI alone group (both P<0.05). However, in DBI with SBI group, there was a significant decrease of the number of mGluR2, 3 positive neurons at 6 hours after injury and the peak happened at 24 hours after injury (both P<0.05). CONCLUSION: mGluR2, 3, factors with the function of protecting brain, might play an important role in the path physiology of DBI and SBI.